A quantitative histologic analysis of ventricular septal architecture was undertaken at necropsy in patients with hypertrophic cardiomyopathy and patients with other heart diseases. Disorganization of cardiac muscle cells occurred more commonly and to a significantly greater extent in patients with hypertrophic cardiomyopathy; disorganization involving greater than or equal to 5% of the septal tissue section strongly suggested this diagnosis. Extensive cardiac muscle cell disorganization in the ventricular septum is probably a morphologic manifestation of the genetic defect in hypertrophic cardiomyopathy.